Menopausal syndrome is related to endocrine, somatic, and psychological changes that occur as the hormonal balance in the female body changes and the menstrual cycle ceases due to the senescence of the ovaries. Menopausal syndrome includes a number of varying and often highly distressing symptoms such as hot flashes, headaches, joint pain, myalgia and general malaise. In particular, hot flashes are a frequent symptom, experienced by more than 50% of menopausal women, and can persist for several years after menopause. For some women, menopausal symptoms are mild and manageable by making life-style changes, including more exercise, dietary changes and stress management, or by using alternative therapies such as acupuncture, massage or chiropractic therapy. For many others, however, symptoms are much more severe and interfere substantially with daily activities or sleep, requiring more potent treatment.
The main treatment to date for menopausal symptoms is the use of hormone-therapy such as estrogen alone, estrogens combined with progesterone, or phytoestrogens. However, the use of estrogens is associated with potentially significant health risks including blood clots, cardiovascular disease, stroke and slight increase in risk of breast cancer when estrogen is taken together with progesterone. Due to concerns about these adverse effects and the fact that hormone-therapy is contraindicated in women with breast cancer, interest in alternative medications to treat menopausal symptoms has been increasing.
Various known, non-hormonal agents have been tested for their efficacy in treating menopausal symptoms (Nelson et al., JAMA 295 (17): 2057-71 (2008)). Among these, antidepressants from classes of medications known as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), including venlafaxine (Effexor), paroxetine (Paxil), fluoxetine (Prozac), citalopram (Celexa) and others, have been found to relieve hot flashes in some clinical trials. However, they are not as efficient as hormone-therapy and adverse effects such as nausea and insomnia have been reported. Compounds that bind to the α2δ subunit of a voltage gated calcium channel such as gabapentin have also been described as treatment for hot flashes, nausea, emesia and fever (see, e.g., U.S. Pat. No. 6,310,098). Gabapentin is approved as an anti-epileptic agent, and has also been used in the treatment of neurogenic pain, restless legs syndrome, essential tremor, bipolar disorder and migraine (Morris GL, Epilepsia 40:S63-S70 (1999)). Gabapentin was only moderately effective in treating hot flashes compared to hormone-therapy and side-effects including somnolence, dizziness and peripheral edema were common (Guttuso et al., Obstet Gynecol, 101:337-345 (2003)). Contradictory results have been reported for clonidine, an a-adrenergic agonist, which reduced hot flashes in some trials, but showed no effect in others. Even though these drugs appeared to have some efficacy against hot flashes, they were not as potent as hormone-therapy and all caused substantial adverse effects. Additional therapies to reduce hot flashes have been proposed including traditional Chinese medicine (WO 2007/081293), leucine (U.S. Pat. No. 6,245,812), ingestible material comprising a herbal complex (U.S. Pat. No. 5,874,084), and luteinizing-hormone-releasing hormone antagonists, (U.S. Pat. No. 6,703,367). However, to date their efficacy and safety has not been thoroughly assessed.
Menopausal symptoms other than hot flashes such as osteoporosis and raised total and LDL cholesterol levels can be treated by selective estrogen-receptor modulators (SERMS), such as raloxifene (U.S. Pat. No. 5,534,526), which selectively bind to and activate the estrogen receptors of some tissues such as bone and block the receptors of others, e.g., breast and uterus. Although raloxifene (Evista) was found to be beneficial for some menopausal symptoms, it does not reduce hot flashes and is associated with serious side effects such as venous thrombembolic events.
Accordingly, there is a need to identify an effective and safe treatment for menopausal symptoms, since current medications are often associated with negative side-effects or fail to show consistent positive results. The invention described herein fulfills this need and provides additional benefits as well.
Arthritis is a group of conditions involving acute or chronic inflammation of a joint, resulting from infection, trauma, degenerative changes, metabolic disturbances, autoimmune disease or other causes. It occurs in various forms, such as osteoarthritis, gout and pseudogout arthritis, ankylosing spondilitis, psoriatic arthritis, systemic lupus erythematosus, septic arthritis or rheumatoid arthritis. Common symptoms of arthritis include swelling, stiffness and constant or recurring pain in one or more joints. In some patients with certain forms of arthritis, symptoms can also include fever, gland swelling, weight loss, fatigue, feeling unwell, and even symptoms from abnormalities of organs such as the lungs, heart, or kidneys.
The most common type of arthritis is osteoarthritis. This type of arthritis affects an estimated 21 million adults in the United States. Osteoarthritis primarily affects cartilage, which is the tissue that cushions the ends of bones within the joint. In osteoarthritis, the cartilage begins to fray and may entirely wear away. Osteoarthritis can cause joint pain and stiffness. Disability results most often when the disease affects the spine and the weight-bearing joints (the knees and hips). Apart from heat application, weight control and appropriate exercise and rest, as well as dietary supplements, additional medications to reduce pain and inflammation in patients suffering from osteoarthiritis include acetaminophen, non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, napoxen or COX-2 selective inhibitors), cortocosteroids (nowadays avoided), and narcotics for severe pain.
The many forms of arthritis make up the most common chronic illness in the United States. For some types of arthritis, the underlying cause has not yet been identified and therefore only symptomatic treatments are being developed. Current treatments include a wide variety of medications due to the variability in symptoms, many of which are associated with risks and are beneficial only in certain groups of patients. Accordingly, there is a need to find medications with high efficacy for various arthritic symptoms and low risks and side-effects. The invention described herein fulfills this need and provides additional benefits as well.
All references cited herein, including, without limitation, patents, patent applications and scientific references, are hereby incorporated in their entirety.